The present invention relates to treating endogenous, painful gastrointestinal conditions, such as abdominal migraine and irritable bowel syndrome, which involve neither inflammation nor ulcers. "Endogenous" in this context denotes a condition that is not attributed to an exogenous casual factor such as a food allergy, a bacterial or viral infection, a parasitic infestation, a drug reaction or trauma. More specifically, the present invention relates to treating a patient suffering from such a condition with a pharmaceutically effective amount of a mast cell degranulation-blocking agent.
The phrase "abdominal pain" indicates pain associated with the gastrointestinal tract. Functional abdominal pain usually is classified either as dyspepsia not associated with ulcers or as irritable bowel syndrome.
Irritable bowel syndrome (IBS), also known as "spastic colon" and "mucous colitis," is an intestinal motility disorder and ranks among the most common pathological conditions of the intestine. IBS is characterized by periodic or chronic bowel symptoms which include abdominal pain, diarrhea, constipation, a sense of incomplete evacuation, bloating, and excess gas sensation. This disorder seems to afflict type A (highly driven, perfectionist) personalities predominantly, and is two to five times more prevalent in women (20 times higher in Jewish women) than in men. It affects about 3 percent of the population. Drossman, Hospital Practice 93:95-108 (1988).
Pain and flatulence are the most prominent symptoms in patients suffering from IBS. The pain is usually situated in the left lower quadrant or suprapubically. It may be worse just before defecation and may lessen slowly afterward. Certain foods may precipitate the symptoms. When diarrhea is the main complaint, the stool often is watery but not bloody. The diarrhea frequently is worst in the morning and improves during the day. Some patients complain of pain in the left upper quadrant that is often brought on by meals and is very consistent in nature. In these patients, plain abdominal X-rays demonstrate air in the splenic flexure. Although this variant of IBS has been called "splenic flexure syndrome," there is no evidence that its pathogenesis differs from that of other manifestations of the disorder.
Many patients relate an exacerbation of symptoms to episodes of emotional stress. Fear of underlying cancer is common. In children of school age, IBS presents primarily with pain. Pain is usually periumbilical or in the left lower quadrant and is cramping in nature.
Many patients also experience abdominal pain that is endogenous but that is associated with nausea, bowel peristalsis and flatulence without diarrhea or constipation, the symptoms commonly seen with IBS. Such abdominal pain also can be associated with classic symptoms of migraine, such as one-sided headache with possible involvement of one eye and visual disturbances in that eye. Axon et al., J. Clin. Gastroenterol. 13: 615-16 (1991). By the same token, about 30-50% of patients diagnosed with IBS have frequent headaches, as compared to less than 15% in the control population. Watson et al., Can. Med. Assoc. J. 118: 387-98 (1978); Whorwell et al., Gut 27: 37-40 (1986). Finally, abdominal pain and associated symptoms can occur in the absence of a headache and still be considered a "migraine equivalent," especially in children. Lundbert, Headache 15: 122-25 (1975).
It is appropriate, therefore, to consider the pathophysiology and therapy of the category of endogenous, painful gastrointestinal conditions of non-inflammatory, non-ulcerative origin, including but not limited to abdominal migraine and IBS.
There is no effective therapy for IBS or related, endogenous gastrointestinal conditions. Thus, while various compounds have been described as useful in treating IBS, including 9H-fluorenyl-substituted amino acid derivatives (U.S. Pat. No. 5,079,260), benzodiazepine derivatives (U.S. Pat. No. 4,970,207), certain substituted sulfonamides (European application No. 0 404 440), and mu opiate receptor antagonists or "blockers" (U.S. Pat. No. 4,684,620), none of the disclosed treatment approaches in fact have proven successful. See, for example, J. Gastroenterol. 95: 232-41 (1988).
Similarly, no effective remedy exists for abdominal migraine. Development of a treatment has been hindered in part by the fact that the condition often presents without headache and any of the prodromal symptoms (nausea, vomiting, photophobia, sonophobia) typically associated with ordinary migraine.
For example, agents that prevent vasodilation, such as the .beta.-blocker propranolol, seem not to work, since the abdominal pain appears not to be associated with the vasculature, in contrast to the migraine headache. By the same token, none of the drugs used prophylactically or acutely (symptomatically) for the treatment of migraine headaches would be expected to work, since the prophylactic agents prevent vasodilation while the acute agents constrict dilated vessels. Moreover, drugs effective against migraine headaches must cross the blood-brain barrier, while a drug effective against abdominal migraine would be concentrated preferentially in the intestine. Also, intracranial mast cells which have been associated with migraine headaches, see Theoharides, Life Sciences 46: 607-17 (1980), and U.S. Pat. No. 5,250,529, differ from gastrointestinal mast cells. For instance, the former but not the latter are inhibited by disodium cromoglycate. Pierce et al., J. Immunol. 128: 2481-86 (1982); Labracht-Hall et al., Neuroscience 39:199-207 (1990).